Original article 1465
Incidence of hypertension in individuals with different blood
pressure salt-sensitivity: results of a 15-year follow-up study
Gianvincenzo Barbaa, Ferruccio Gallettib, Francesco P. Cappuccioc,
Alfonso Siania, Antonella Veneziab, Marco Versierob, Elisabetta Della Valled,
Paolo Sorrentinob, Giovanni Tarantinob, Eduardo Farinarod and
Pasquale Strazzullob
Objective To evaluate the incidence of hypertension and
the rate of decline in renal function in a sample of 47 Olivetti
Heart Study (OHS) participants whose blood pressure (BP)
salt-sensitivity and renal tubular sodium handling had been
assessed in 1987–88.
Methods During the 2002–04 OHS follow-up examination,
medical history, physical examination and blood and urine
sampling were performed in 36 of the 47 participants to the
baseline study (age 60 W 6 years; average followup U 15.1 W 0.6 years). The renal length was measured in
23 participants by kidney ultrasonography. Based on the
baseline salt-sensitivity evaluation, the subjects were
classified into a lower salt-sensitivity (LSS, n U 20) and a
higher salt-sensitivity group (HSS, n U 16).
Results In comparison with the LSS group, HSS
participants had a significantly higher incidence of
hypertension (87.5 versus 50.0%, P U 0.02), a higher
glomerular filtration rate (median, first to fourth quartile:
81.9, 72.3–95.2 versus 72.3, 59.9–81.2 ml/min; P U 0.03)
and greater kidney length (median, first to fourth quartile:
68.2, 63.3–72.1 versus 61.9, 58.7–62.7 mm/m of height;
P U 0.003). The incidence of hypertension remained
significantly higher in HSS individuals after adjustment for
Introduction
age, intercurrent changes in body mass index and baseline
blood pressure on low sodium diet (P U 0.04).
Conclusion Our findings indicate that individuals with
higher BP salt-sensitivity have a higher rate of incident
hypertension and suggest an altered renal tubular sodium
handling involving a trend to increased glomerular filtration
rate and blood pressure over time as a possible mechanism.
J Hypertens 25:1465–1471 Q 2007 Lippincott Williams &
Wilkins.
Journal of Hypertension 2007, 25:1465–1471
Keywords: blood pressure, glomerular filtration rate, prospective study,
renal function, sodium dependent hypertension
a
Epidemiology and Population Genetics, Institute of Food Sciences, CNR,
Avellino, bDepartment of Clinical and Experimental Medicine, ‘Federico II’
University of Naples, Naples, Italy, cDivision of Clinical Sciences, Clinical
Sciences Research Institute, Warwick Medical School, Coventry, UK and
d
Department of Preventive Medical Sciences, ‘Federico II’ University of Naples,
Naples, Italy
Correspondence to Gianvincenzo Barba, Epidemiology and Population Genetics,
Institute of Food Science, National Research Council, Via Roma 52A/C, 83100
Avellino, Italy
Tel: +39 0825299 353; fax: +39 0825299 423; e-mail: gbarba@isa.cnr.it
Received 3 August 2006 Revised 4 February 2007
Accepted 15 February 2007
A heterogeneous blood pressure (BP) response to
changes in dietary sodium chloride intake, a phenomenon generally referred to as BP salt-sensitivity, is
observed in both hypertensive patients and normotensive
individuals [1–3]. On the basis of the feature characteristics of well described forms of monogenic hypertension
[4–6], it is conceivable that a different ability of the
kidney to excrete sodium and water is involved in this
phenomenon [7].
proximal tubular sodium reabsorption and higher glomerular filtration rate (GFR) when on habitual high sodium
diet compared to those with a lower degree of saltsensitivity. These alterations were no longer apparent
when the subjects were placed on a low sodium diet
(40 mmol Na/day for 3 days). We speculated that the
trend to greater tubular sodium reabsorption detected
in the more salt-sensitive subjects elicited humoral
adaptive responses to overcome the difficulty in sodium
excretion at the cost of an increase in BP and GFR.
We have previously reported on BP, renal function and
tubular sodium handling in a sample of healthy normotensive male volunteers drawn from a middle-aged male
working population in 1987–88 [3]. Our results showed
that those with higher salt-sensitivity, estimated by their
BP response to low salt diet, had increased BP, greater
Other studies have reported increased GFR and/or
intraglomerular pressure in salt-sensitive hypertension
[8–13]. In turn, hyperfiltration could heighten susceptibility to renal function deterioration and actually it has
been found to be associated with early organ damage in
hypertensive patients [14].
0263-6352 ß 2007 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1466 Journal of Hypertension
2007, Vol 25 No 7
The aim of the present study was to evaluate BP and
renal function in the same individuals studied in 1987–88
[3] during the 2002–04 follow-up examination of the
Olivetti Heart Study (OHS), an average of 15 years after
the original observation.
Patients and methods
elemental lithium. On the following morning, a timed
fasting urine collection was performed and a blood
sample was obtained at the mid-point of the collection
for the measurement of serum and urinary lithium and
creatinine concentration. Standard formulae were used to
calculate the rates of fractional proximal and distal
sodium reabsorption [3].
Baseline evaluation (1987–88)
Forty-seven healthy normotensive male employees of
the Olivetti Factory in Pozzuoli (Naples) volunteered
to participate in the above-mentioned study of the
association between salt-sensitivity, BP and renal function carried out in 1987–88 [3]. They were seen at the
medical centre located within the factory premises; the
examinations were performed in the morning. Participants were asked to refrain from smoking and from
engaging in strenuous physical exercise in the hours
preceding the examination. At the time of the visit, they
were following their habitual diet and were fasted for at
least 13 h. They underwent a physical examination, complete anthropometric measures and a blood test. Body
weight and height were measured on a standard beam
balance scale with an attached ruler. Body weight was
measured to the nearest 0.1 kg and height was measured
to the nearest cm with subjects wearing only light indoor
clothing without shoes. Body mass index (BMI) was
calculated as weight (kg) divided by the square of the
height (m2). BP was measured in a quiet and comfortable
room using a standard mercury sphygmomanometer by a
well trained operator. After the subject had remained
seated for at least 10 min, three consecutive measures
were taken of systolic (SBP) and diastolic (DBP) blood
pressure at 2-min intervals and the last two measurements
were used for the analysis. Mean BP (MBP) was calculated
as DBP þ 1/3SBP. A fasting venous blood sample was taken
in the seated position without stasis after the BP measurements. The blood specimens were immediately centrifuged and stored at 70 8C until analysed.
Evaluation of salt-sensitivity and renal tubular sodium
handling at the 1987–88 (baseline) examination
The evaluation of salt-sensitivity was performed at baseline (1987–88 examination) and was based on the individual MBP change upon shifting from the NaCl-rich
habitual diet (averaging 184 9 mmol/24 h) to a 3-day salt
restricted diet (averaging 69 5 mmol/24 h). Based on the
median value of MBP change in the whole study population, we identified a group of individuals with a lower
level of salt-sensitivity (LSS, n ¼ 24; MBP decrease less
than 5.7%) and a group with higher salt-sensitivity (HSS,
n ¼ 23; MBP decrease greater than 5.7%).
An evaluation of segmental renal tubular sodium handling was also made at baseline both on high and low NaCl
diet. To this purpose, on the evening before the visit, the
participants took a 300 mg lithium carbonate capsule
(Carbolithium; IFI, Milan, ltaly) delivering 8.1 mmol of
Follow-up (2002–04 examination)
Thirty-six of the 47 participants in the baseline (1987–
88) observation (LSS ¼ 16, HSS ¼ 20) were re-examined
during the 2002–04 OHS follow-up examination (mean
follow-up length ¼ 15.1 0.6 years). Of the 11 subjects
lost to follow-up, four had changed their residence and
could not be located, three refused to participate, one
was unable to attend because of a serious invalidating
condition and three patients had died before the followup visit (one due to coronary heart disease and two due to
neoplastic diseases).
The follow-up visits were performed at the Outpatient
Clinic of the Department of Clinical and Experimental
Medicine, Federico II University of Naples Medical
School between November 2002 and June 2004. Anthropometric indices and BP were measured adopting the
same procedures used at baseline observation. The diagnosis of hypertension was based on the finding of values
of 140 mmHg systolic and/or 90 mmHg diastolic BP
or on the current assumption of antihypertensive medications prescribed by the participants’ family doctors.
Segmental tubular sodium handling was not evaluated at
the follow-up examination. However, a 24-h urine collection was obtained from each participant for the measurement of sodium excretion, taken as an estimate of daily
dietary sodium intake, and of urinary albumin excretion
rate (AER). Urinary sodium concentration was measured
by flame photometry and urinary albumin concentration
by an immunoturbidimetric assay (Horiba ABX Diagnostics, Rome, Italy) using a Cobas-Mira analyser (Roche
Instrument Center, Rotkreuz, Switzerland).
Kidney ultrasonography was carried out only at the 2002–
2004 follow-up examination in a subsample of 23 participants by a duplex–Doppler apparatus (Esaote-Hitachi
570 AU; Hitachi Medical Corporation, Japan) with
convex 3.5-MHz transducer. Patients’ position always
included supine or lateral decubitus. Usually, a combination of intercostal and sub-costal approaches were
necessary to obtain, in the coronal plane, the outcome
measurements [i.e. the maximal bipolar and the kidney
parenchymal (cortex plus medullary pyramids) thickness
diameters].
To allow for the comparison of renal function at baseline
and at 15-year follow-up, GFR was assessed in both
occasions by the calculation of creatinine clearance
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Salt-sensitivity and risk of hypertension Barba et al.
according to the Cockcroft–Gault formula [15]:
1467
with LSS participants. These differences were not apparent when the subjects were on a low-sodium diet.
ð½ð140 age ðyearsÞ
½weight ðkgÞÞ=½72 serum creatinine ðmg=dlÞ
At baseline, serum creatinine was measured both on
habitual and on low NaCl diet.
Statistical analysis
Data were expressed as median and first to fourth quartile, or as otherwise indicated. The relationships between
BP salt-sensitivity determined at baseline and long-term
outcomes (i.e. rate of hypertension, decline in renal
function and kidney morphology) were evaluated by
non-parametric Spearman correlation analysis. Because
kidney length was strictly dependent on body size, its
values were adjusted for height. Between-group comparisons were performed by Mann–Whitney test for
unpaired data. Comparison between frequencies of specified conditions was performed by the chi-squared test.
The predictive value of BP salt-sensitivity on the rate of
hypertension was evaluated by logistic regression analysis
adjusting for possible confounders (age, family history of
hypertension, BMI changes over the follow-up period,
baseline BP). Because AER distribution disclosed significantly from normality, log-transformed AER values
were used for statistical analysis. P < 0.05 was considered
statistically significant.
The study protocol was approved by the local ethics
committee and all participants gave their informed consent to participate in both occasions.
Results
Table 1 shows the baseline characteristics of the LSS and
HSS subjects undergoing the follow-up study. The HSS
group had a trend to greater BMI compared with the LSS
group. On high-salt diet, a significantly higher BP and a
trend to greater GFR were observed in HSS compared
Table 1
The duration of follow-up was similar for the two groups.
At follow-up examination, only slight changes were
observed in BMI [HSS ¼ þ1.6 (0.7–3.1), LSS ¼ þ0.9
(0.7–2.1) kg/m2, P ¼ 0.26]. Urinary 24-h sodium
excretion was similar in the two groups [HSS ¼ 129
(103–148), LSS ¼ 141 (108–193) mmol/24 h, P ¼ 0.22].
Likewise, no difference was detected in family history
of hypertension (at least one relative affected, HSS ¼
37.5, LSS ¼ 62.5%, P ¼ 0.10).
Blood pressure
There were 24 (68.6%) incident cases of hypertension in
the entire sample, 14 in the HSS (87.5%) and ten in the
LSS group (50.0%), chi-squared ¼ 5.625; P ¼ 0.018
(Fig. 1a). The percentage of subjects aware of being
hypertensive and taking regular antihypertensive drug
therapy at follow-up visit was five-fold greater in the HSS
than in the LSS group [8/16 (50%) versus 2/20 (10.0%),
Fisher’s exact test: P ¼ 0.01].
To rule out the influence of confounders in the association between the degree of salt-sensitivity and incidence
of hypertension, a logistic regression model was used with
incident hypertension (yes/no) as dependent variable,
salt-sensitivity degree category (LSS/HSS) as independent variable and the following covariates: family history
of hypertension (at least one relative affected, yes/no),
age (years), BMI changes (%) during the follow-up period
and BP (mmHg) on low NaCl diet at baseline. According
to this model (Table 2, Model 1), salt-sensitivity assessed
at baseline was a significant independent predictor of the
incidence of hypertension. Statistical significance was
lost when in the same model the baseline BP on low
NaCl diet was replaced by the baseline BP recorded on
high NaCl intake (Table 2, model 2). Baseline diastolic
BP, both on low and high NaCl diet was also a significant
predictor of hypertension.
Baseline (1987/88 follow-up) characteristics of the salt-sensitive and the salt-resistant group
LSS (n ¼ 20)
Age (years)
Height (m)
Body weight (kg)
BMI (kg/m2)
BP on high NaCl diet (mmHg)
BP on low NaCl diet (mmHg)
D Mean BP from high-to-low NaCl diet (%)
GFR on high NaCl diet (ml/min)
GFR on low NaCl diet (ml/min)
FPRNa on high NaCl diet (%)
FPRNa on low NaCl diet (%)
FDRNa on high NaCl diet diet (%)
FDRNa on low NaCl diet (%)
HSS (n ¼ 16)
Median
1st to 4th quartile
Median
1st to 4th quartile
46.0
1.71
74.5
25.5
117/81
118/79
2.3
86.1
86.4
75.8
81.8
94.4
98.5
42.2–51.5
1.64–1.76
65.5–81.5
22.6–26.7
110–123/76–86
112–123/77–82
5.0, 3.0
77.9–94.1
79.1–93.7
73.8–79.9
79.1–84.2
93.5–96.7
97.9–99.9
42.0
1.66
74.0
26.3
128/87M
111/75M
10.8
92.1
90.3
75.9
80.5
96.4
98.7
40.2–45.0
1.64–1.70
68.5–83.2
25.4–28.2
115–133/82–89
109–119/71–81
16.1, 8.7
82.1–113.2
81.8–102.5
71.8–78.3
75.8–83.5
95.9–97.0
98.3–99.1
M
P < 0.05. BP, Blood pressure; BMI, body mass index; GFR, glomerular filtration rate; FPRNa, fractional proximal reabsorption of sodium; FDRNa, fractional distal
reabsorption of sodium; HSS, higher salt-sensitivity; LSS, lower salt-sensitivity.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1468 Journal of Hypertension
2007, Vol 25 No 7
Fig. 1
Logistic regression model of predictors of incidence of
hypertension during 15-year follow-up in individuals with different
salt sensitivity of blood pressure
Table 2
Model 1
Salt sensitivity (LSS/HSS)
Age (years)
FHþ (yes/no)
BMI change (1987/88 to 2002/04) (%)
Systolic BP on low NaCl diet (mmHg)
Diastolic BP on low NaCl diet (mmHg)
Model 2
Salt-sensitivity (LSS/HSS)
Age (years)
FHþ (yes/no)
BMI change (1987/88-2002/04) (%)
Systolic BP on high NaCl diet (mm Hg)
Diastolic BP on high NaCl diet (mm Hg)
Beta SE
P
5.188 2.208
0.320 0.179
1.764 1.370
0.044 0.303
0.013 0.084
0.433 0.215
0.02
0.07
0.20
0.88
0.87
0.04
1.213 1.232
0.215 0.121
1.076 1.299
0.262 0.292
0.001 0.071
0.303 0.144
0.32
0.07
0.41
0.37
0.90
0.03
FHþ, positive family history of hypertension (at least one relative affected); BMI,
body mass index; BP, blood pressure; HSS, higher salt-sensitivity; LSS, lower saltsensitivity.
higher mean longitudinal kidney diameter (expressed as
the average of the longitudinal diameter of the left and
the right kidneys) as either absolute (Fig. 1c) or heightadjusted values [HSS: 68.2 (63.3–72.1); LSS: 61.9 (58.7–
62.7) mm/m of height; Mann–Whitney, P ¼ 0.003].
(a) Incidence of hypertension, (b) glomerular filtration rate and
(c) kidney length (expressed as the average of the longitudinal diameter
of the left and the right kidney), estimated during the 2002–04 followup of the Olivetti Heart Study in individuals, normotensive at baseline,
with different blood pressure salt-sensitivity assessed at baseline
examination (1987–88). Incidence of hypertension: Pearson chi
squared ¼ 5.625; P ¼ 0.018. Glomerular filtration rate: Mann–Whitney,
P ¼ 0.03. Kidney length: n ¼ 23 (LSS ¼ 11; HSS ¼ 12); Mann–
Whitney, P ¼ 0.03; Data are expressed as median and first to fourth
quartile. LSS, Lower salt-sensitivity; HSS, higher salt-sensitivity.
Kidney function and morphology
The GFR was greater in the HSS group compared to the
LSS group (Fig. 1b) at follow-up examination. When
comparing GFR at baseline and after 15-year followup, however, a similar decrease was observed in the
two groups [LSS: 1.0 (1.8, 0.5); HSS: 0.9 (1.2,
0.6)% of baseline value per year, P ¼ 0.46].
AER, taken as an index of renal damage, was higher in the
HSS than in the LSS group, but the difference was not
statistically significant [HSS: 8.9 (3.9–17.7); LSS: 6.9
(3.8–17.4) mg albumin/24 h; P ¼ 0.38].
Kidney ultrasound scan was performed in 23 participants
(LSS ¼ 11; HSS ¼ 12). HSS participants had significantly
Salt-sensitivity was inversely associated with kidney
length as both absolute (r ¼ –0.476, P ¼ 0.02) and
height-adjusted values (r ¼ –0.446, P ¼ 0.03). There
was also a direct association between kidney length
and GFR, either expressed as unadjusted (r ¼ 0.653;
P ¼ 0.001) or height-adjusted kidney length (r ¼ 0.425;
P ¼ 0.04). Renal parenchymal thickness was similar in the
two groups [LSS: 14.3 (12.5–17.0); HSS: 17.5 (14.7–
18.4) mm; P ¼ 0.10], also after adjustment for kidney
length.
Supplemental analysis with adoption of a different
criteria for definition of salt-sensitivity
We carried out supplemental analyses using a second
criteria for definition of salt-sensitivity (i.e. a 10 mmHg
fall in MBP when shifting from high to low sodium diet),
according to Weinberger et al. [16]. By so doing, two
groups were identified, respectively, 14 salt-sensitive and
22 salt-resistant individuals. These two groups were
comparable with each other with respect to age, BMI
and length of follow-up. GFR was higher in salt-sensitive
individuals at baseline [93.3 (82.4–114.3) versus 86.1
(76.3–93.5) ml/min; P ¼ 0.06] and at the follow-up examination [82.0 (72.1–97.5) versus 73.6 (60.2–96.5) ml/min;
P ¼ 0.04]. Mean longitudinal kidney diameter was significantly higher in salt-sensitive than in salt-resistant
subjects [111.0 (105.0–121.0) versus 102.2 (98.4–
109.2) mm; P ¼ 0.03]. The incidence of hypertension
was 86% (12/14) versus 54% (12/22) (P ¼ 0.07) and that
of current antihypertensive treatment was 43% (6/14)
versus 18% (4/22) (P ¼ 0.14) in the salt-sensitive and
the salt-resistant groups, respectively. At logistic
regression analysis, salt-sensitivity defined by this criteria
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Salt-sensitivity and risk of hypertension Barba et al.
was a significant predictor of the incidence of hypertension (P ¼ 0.04), controlling for age, BMI change, followup length, family history of hypertension and baseline
BP on low sodium diet.
Discussion
The present study evaluated the incidence of arterial
hypertension and renal function outcomes over 15 years
in a group of originally normotensive and clinically
healthy men with different BP salt-sensitivity. Our main
finding was that the incidence of hypertension was significantly higher among individuals with a higher degree
of salt-sensitivity at baseline compared to subjects with
lower salt-sensitivity. Although previous studies analysed
cardiovascular morbility in hypertensive patients [17] and
total mortality in both normotensive and hypertensive
individuals [18] according to BP salt-sensitivity, to our
knowledge, this is the first demonstration of an independent predictive value of salt-sensitivity with regard to the
probability of normotensive individuals to develop high
BP in the future. These results provide further support to
the role of salt-sensitivity and indirectly of excess dietary
salt intake in the pathogenesis of hypertension.
In general, the occurrence of hypertension was high in
this study population. At the end of the follow-up period,
almost all the subjects in the salt-sensitive group had
become hypertensive and half of them were on regular
antihypertensive treatment prescribed by their family
doctor. On multivariate analysis, it was found that the
degree of salt-sensitivity was a significant independent
predictor of the incidence of hypertension during the
15-year follow-up period. The predictive ability of saltsensitivity was not confounded by the baseline BP value
obtained on low salt diet, a condition in which the blood
pressures of the LSS and HSS group were similar. By
contrast, this predictive ability was lost when the baseline
BP values during high sodium diet were included as
covariate in the regression model: this is not surprising
because these values were significantly different in the
two groups as they were the expression of the different
salt-sensitivity.
Although it is known that overweight and obesity are
associated with alterations in renal sodium handling [19]
and with BP salt-sensitivity [20–22], the difference in the
risk of hypertension between HSS and LSS individuals
was independent of the relatively small changes in body
weight that occurred during the follow-up period.
The criteria used to define salt-sensitivity in our study
were arbitrary. Indeed, no universally recognized definition for salt-sensitivity has yet been delivered. Previous
studies in normotensive individuals [23] adopted a 5% fall
in BP shifting from high to low sodium diet to define
salt-sensitivity, a value that is very similar to the median
of MBP response to the change in sodium intake
1469
(corresponding to a 5.7% BP difference) in our study.
As, however, in several other published studies, mostly
dealing with hypertensive patients, a 10 mmHg BP fall
on a low- compared to a high-salt diet was adopted as a
cut-off to define BP salt-sensitivity [16,18], supplemental
analyses were produced using this second criteria. Even
so, salt-sensitivity was a significant independent predictor
of the incidence of hypertension on multivariate analysis.
In addition, the group of ‘salt-sensitive’ individuals identified by this cut-off displayed significantly higher GFR,
and significantly greater mean renal diameter at followup, in the same way as when using the median of BP
response as a salt-sensitivity cut-off.
Another novel finding of the present study was that
individuals with greater salt-sensitivity, who had an
increased rate of proximal tubular sodium reabsorption
and a greater GFR at baseline compared to the LSS group
[3], maintained an increased GFR at the 15-year followup visit. On this occasion, it was found that their higher
GFR was associated with greater kidney length. Unfortunately, measurements of renal tubular sodium handling
were not available at this time.
These results, in accordance with the evidence provided
by several forms of monogenic hypertension [4–6] and
by studies in essential hypertensive patients [12–13],
support the contention that BP salt-sensitivity is the
expression of an alteration of renal sodium handling
impairing the ability of the kidney to excrete a large
dietary sodium load and leading to a progressive increase
in BP [3,24]. The renal sodium handling abnormality and
the increased GFR were apparent before hypertension
developed [3].
Very few data are available in the literature on the
relationships between salt-sensitivity, glomerular hyperfiltration and risk of hypertension. Former kidney
donors, who feature renal compensatory hypertrophy
and increased single-nephron GFR, were found to have
an increased risk of hypertension in some but not all
studies [25–27]. Nevertheless, in these subjects, a
persistent relative increase in GFR was associated with
increased kidney size [27]. Hyperfiltration and/or
increased intraglomerular pressure have been reported
in hypertensive blacks and in other forms of salt-sensitive
hypertension [8]. According to Schmieder et al. [14],
hyperfiltration per se is an early marker of target organ
damage. Moreover, in a 6-year follow-up study in essential hypertensive patients with normal renal function, it
was found that the higher the GFR at baseline, the
greatest the increase in serum creatinine at follow-up
[28]. However, our prospective data in normotensive
individuals did not confirm this finding. In spite of the
greater incidence of hypertension in HSS individuals,
the decline in GFR was similar in HSS and LSS participants, with GFR remaining higher in the group of
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1470 Journal of Hypertension
2007, Vol 25 No 7
subjects with higher degree of salt-sensitivity: this finding
was corroborated by the absence of significant differences
in renal parenchymal thickness and in the albumin
excretion rate. This somewhat unexpected result might
be explained by the relatively young age of our study
population, by the absence of both hypertension and
diabetes at baseline examination and by the protective
effect exerted by antihypertensive treatment, as
expected based on the results of studies carried out in
sodium dependent forms of hypertension [29,30]. Moreover, there is evidence that renal deterioration following
hyperfiltration is generally associated with a reduction of
the total number of nephrons and with loss of renal mass
[31–34]. Although our data must be interpreted with
caution due to the small sample size and the absence
of baseline measurement of morphological parameters,
they are in accordance with studies in kidney donors and
in patients with solitary kidneys due to nephrectomy or to
unilateral renal agenesis, which do not show a higher
incidence of renal insufficiency until a further renal mass
loss occurs [31–32].
ated with a pattern characterized by an increased risk of
hypertension, altered proximal tubular sodium handling,
enhanced GFR and increased kidney size. Further
follow-up of the study participants is warranted to establish whether these alterations will be followed by detectable renal function deterioration in the future.
Acknowledgements
The contribution of the components of the Olivetti Study
Research Team to this study is gratefully acknowledged:
A. Barbato, M. Bartolomei, L. D’Elia, G. De Luca, M.C.
Gerardi, O. Russo, R. Iacone, P. Russo and A. Venezia.
The Steering Committee of the Olivetti Heart Study
comprises: P. Strazzullo (co-ordinator), F. P. Cappuccio,
E. Farinaro, A. Siani and G. Barba. Part of the study data
were previously presented at the ESH 2006 Meeting.
The study was supported in part by grants from MIUR
(Italian Ministry of University and Research, COFIN
2004 and FIRB 2001) (LD1).
There are no conflicts of interest.
Limitations
The sample under study was composed of white men
only; thus, our findings cannot be extrapolated to women,
nor to other ethnic groups.
The assessment of salt-sensitivity was made only at
baseline and was based on the BP response to a very
short period of dietary salt restriction. Moreover, both at
baseline and at follow-up, BP was measured very carefully according to a well standardized protocol; however,
measurements could not be repeated on a second separate occasion. These limitations were dictated by the
epidemiological nature of our study which did not allow
the performance of a second examination at a short
distance of time. We acknowledge that they can make
the evaluation of both BP salt-sensitivity and incidence of
hypertension less accurate than desirable. Nevertheless,
we believe it is most unlikely that they would explain our
main findings. It is expected that inaccuracies in the
measurement of any given variable due to introducing
a larger regression dilution bias should impair the detection of true biological associations. The same is also
conceivable if we consider, as a further limitation of
our study, the relatively small sample size.
References
1
2
3
4
5
6
7
8
9
10
11
Finally, kidney ultrasonography was performed only at
follow-up examination in a limited number of subjects:
therefore, we do not know whether differences in kidney
dimensions preceded the occurrence of hypertension.
12
13
In conclusion, the present study provides long-term
prospective data on the incidence of hypertension and
renal function outcomes in normotensive individuals
with normal renal function at baseline and different
degree of BP salt-sensitivity. Salt-sensitivity was associ-
14
15
Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension
1996; 27:481–490.
Strazzullo P, Galletti F, Dessi-Fulgheri P, Ferri C, Glorioso N, Malatino L,
et al. Prediction and consistency of blood pressure salt-sensitivity as
assessed by a rapid volume expansion and contraction protocol.
Salt-Sensitivity Study Group of the Italian Society of Hypertension.
J Nephrol 2000; 13:46–53.
Barba G, Cappuccio FP, Russo L, Stinga F, Iacone R, Strazzullo P. Renal
function and blood pressure response to dietary salt restriction in
normotensive men. Hypertension 1996; 27:1160–1164.
Ulick S, Ramirez LC, New MI. An abnormality in steroid metabolism in a
hypertensive syndrome. J Clin Endocrinol Metab 1977; 44:799–802.
Sutherland DJA, Ruse JL, Laidlaw JC. Hypertension, increased aldosterone
secretion and low plasma renin activity reversed by dexamethasone.
Can Med Assoc J 1966; 95:1109–1119.
Liddle GW, Bledsoe T, Coppage WS. A familial renal disorder simulating
primary aldosteronism but with negligible aldosterone secretion. Trans
Assoc Am Phys 1963; 76:199–213.
De Wardener HE. The primary role of the kidney and salt intake in the
aetiology of essential hypertension, part II. Clin Sci 1990; 79:289–297.
Campese VM, Parise M, Karubian F, Bigazzi R. Abnormal renal
hemodynamics in black salt-sensitive patients with hypertension.
Hypertension 1991; 18:805–812.
Parmer RJ, Stone RA, Cervenka JH. Renal hemodynamics in essential
hypertension: racial differences in response to changes in dietary sodium.
Hypertension 1994; 24:752–757.
Campese VM, Romoff MS, Levitan D, Saglikes Y, Friedler RM, Massry SG.
Abnormal relationship between sodium intake and sympathetic nervous
system activity in salt-sensitive patients with essential hypertension. Kidney
Int 1982; 51:457–464.
Fujita T, Henry WL, Bartter FC, Lake CR, Delea CS. Factors influencing
blood pressure in salt sensitive patients with hypertension. Am J Med
1980; 69:334–344.
Skrabal F, Herholz H, Neumayr M, Hamberger L, Ledochowsky M, Sporer
H, et al. Salt sensitivity in humans is linked to enhanced sympathetic
responsiveness and to enhanced proximal tubular reabsorption.
Hypertension 1984; 6:152–158.
Chiolero A, Maillard M, Nussberger J, Brunner HR, Burnier M. Proximal
sodium reabsorption: An independent determinant of blood pressure
response to salt. Hypertension 2000; 36:631–637.
Schmieder RE, Messerli FH, Garavaglia G, Nunez B. Glomerular
hyperfiltration indicates early target organ damage in essential
hypertension. JAMA 1990; 264:2775–2780.
Cockroft DW, Gault MH. Prediction of creatinine clearance from serum
creatinine. Nephron 1976; 16:31–41.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Salt-sensitivity and risk of hypertension Barba et al.
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
1471
Weinberger MH, Stegner JE, Fineberg NS. A comparison of two tests for
the assessment of blood pressure responses to sodium. Am J Hypertens
1993; 6:179–184.
Morimoto A, Uzu T, Fujii T, Nishimura M, Kuroda S, Nakamura S, et al.
Sodium sensitivity and cardiovascular events in patients with essential
hypertension. Lancet 1997; 350:1734–1737.
Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M. Salt sensitivity,
pulse pressure, and death in normal and hypertensive humans.
Hypertension 2001; 37:429–432.
Strazzullo P, Barba G, Cappuccio FP, Siani A, Trevisan M, Farinaro E, et al.
Altered renal sodium handling in men with abdominal adiposity. A link to
hypertension. J Hypertens 2001; 19:2157–2164.
Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V, Martin M.
The effect of weight loss on the sensitivity of blood pressure to sodium in
obese adolescents. N Engl J Med 1989; 321:580–585.
Egan BM, Stepniakowski K, Nazzaro P. Insulin levels are similar in obese
salt-sensitive and salt-resistant hypertensive subjects. Hypertension 1994;
23 (Suppl):I17.
Kassab S, Kato T, Wilkins FC, Chen R, Hall JE, Granger JP. Renal
denervation attenuates the sodium retention and hypertension associated
with obesity. Hypertension 1995; 25:893–897.
Sullivan JM, Prewitt RL, Ratts TE. Sodium sensitivity in normotensive and
borderline hypertensive humans. Am J Med Sci 1988; 295:370–377.
Barba G, Vallance PJ, Strazzullo P, MacAllister RJ. Effects of sodium intake
on the pressor and renal responses to nitric oxide synthesis inhibition in
normotensive individuals with different sodium sensitivity. J Hypertens
2000; 18:615–621.
Saran R, Marshall SM, Madsen R, Keavey P, Tapson JS. Long-term followup of kidney donors: a longitudinal study. Nephrol Dial Transplant 1997;
12:1615–1621.
Eberhard OK, Kliem V, Offner G, Oldhafer K, Fangmann J, Pichlmay R, et al.
Assessment of long-term risks for living related kidney donors by 24-h
blood pressure monitoring and testing for microalbuminuria. Clin
Transplant 1997; 11:415–419.
Boudville N, Prasad GV, Knoll G, Muirhead N, Thiessen-Philbrook H, Yang
RC, et al. Donor Nephrectomy Outcomes Research (DONOR) Network.
Meta-analysis: risk for hypertension in living kidney donors. Ann Intern Med
2006; 145:185–196.
Schmieder RE, Veelken R, Gatzka GD, Ruuddel H, Schachinger H.
Predictors of hypertensive nephropathy: Results of a six-years follow-up
study in essential hypertension. J Hypertens 1994; 13:357–365.
Laffer CL, Elijovich F. Essential hypertension of Caribbean Hyspanics:
sodium, rennin, and response to therapy. J Clin Hypertens 2002; 4:266–
273.
Wolf G, Butzman U, Wenzel UO. The renin-angiotensin-system and
progression in renal disease: from hemodynamics to cell biology. Nephron
Physiol 2003; 93:P3–P13.
Novick AC, Gephardt G, Guz B, Steinmuller D, Tubbs RR. Long-term
follow-up after partial removal of solitary kidney. N Engl J Med 1991;
325:275–281.
Oldrizzi L, Rugiu C, de Biase V, Maschio G. The solitary kidney:
a risky situation for progressive renal damage? Am J Kidney Dis 1991;
5 (Suppl 1):57–61.
Ots M, Troy JL, Rennke HG, Mackenzie HS, Brenner BM. Impact of the
supplementation of kidney mass on blood pressure and progression of
kidney disease. Nephrol Dial Transplant 2004; 19:337–341.
Abdi R, Dong VM, Rubel JR, Kittur D, Marshall F, Racusen LC. Correlation
between glomerular size and long-term renal function in patients with
substantial loss of renal mass. J Urol 2003; 170:42–44.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.